FGF8 deficient mice have been created to evaluate the role of this factor in pharyngeal and cardiovascular development. Great vessel and outflow tract septation and alignment defects we re found in 95% of the hypomorphic mutant mice;these include persistent truncus arteriosus and interrupted aortic arch. FGF8 is produced in the epithelia surrounding the mesoderm and neural crest-derived mesenchymal cells that populate the pharyngeal arches, and contribute to the cardiac outflow tract and great vessels. We hypothesize that the cardiovascular malformations in Fgf8 mutant mice result from defective FGF8 signaling between the pharyngeal arch ectoderm and endoderm, and the underlying mesenchyme. The objective of this project is to define the molecular and cellular pathways in which FGF8 participates during cardiovascular and pharyngeal development. To determine if mutant phenotypes are due to local deficiency of FGF8 in the arch epithelia, our first aim is to conditionally ablate FGF8 in the ectoderm and endoderm of the developing pharyngeal arches. Aim 2 is to evaluate the formation and evolution of aortic arch arteries and supporting tissues in Fgf8 mutants and define the role of FGF8 during vasculogenesis in the fourth pharyngeal arch. Our third aim is to investigate the molecular and cellular pathways that are dependent on FGF8 during pharyngeal and cardiovascular development by characterizing the alterations in gene expression, proliferation, and survival of pharyngeal neural crest, mesoderm and endoderm in Fgf8 hypomorphic and conditional mutants. We will identify specific populations of FGF- responding cells and determine how their differentiation and behavior are affected by deficiency or absence of FGF8. The array of phenotypes displayed by these FGF8 deficient animals is a remarkably complete phenocopy of human syndromes associated with deletion of chromosome 22q11. Delineation of the pathways in which FGF8 is participates will not only help us to define how those pathways guide normal development of pharyngeal structures, the cardiac outflow tract and great vessels, but will also provide insight into how dysfunction of those developmental programs gives rise to the common and lethal array of birth defects that result from deletion of genes in the human 22g11 region.